Theoretical and Computational Chemistry

The effect of the multiple mutations in Omicron RBD on its binding to human ACE2 receptor and immune evasion: an investigation of molecular dynamics simulations

Authors

  • Leyun Wu Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Liping Zhou Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Mengxia Mo College of Computer Science and Technology, National University of Defense Technology ,
  • Yishui Li College of Computer Science and Technology, National University of Defense Technology ,
  • Jiaxin Han Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Jintian Li Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Yanqing Yang Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Xinben Zhang Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Chunye Gong College of Computer Science and Technology, National University of Defense Technology ,
  • Kai Lu College of Computer Science and Technology, National University of Defense Technology ,
  • Likun Gong Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Chengkun Wu College of Computer Science and Technology, National University of Defense Technology ,
  • Weiliang Zhu Shanghai Institute of Materia Medica, Chinese Academy of Sciences ,
  • Zhijian Xu Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Abstract

SARS-coronavirus-2 (SARS-CoV2) Omicron variant (B.1.1.529) is of great concern to the world due to multiple mutations that may have an impact on transmissibility and immune evasion. Compared to the wild type (WT), there are 15 mutations in the Omicron receptor-binding domain (RBD), 10 of which are in the receptor-binding motif (RBM), where the host angiotensin-converting enzyme 2 (ACE2) interacts directly with. As a comparison, the currently dominant variant Delta (B.1.617.2) only has 2 mutations (L452R and T478K) or an additional E484K mutation in the RBM. As many as 15 mutations in Omicron RBD make it very hard to predict whether the mutations would increase the binding affinity to ACE2, particularly considering that 10 mutations crowded in the RBM. To understand the combinatorial mutation effect on Omicron RBD binding to ACE2 and potential immune evasion, we calculated the binding affinities of the WT/Delta/Omicron RBDs to ACE2 and antibodies with 600 ns molecular dynamics simulations for each system. We found that Omicron RBD has slightly weaker ACE2 affinities than WT RBD (-29.39 ± 2.96 Kcal/mol vs. -33.13 ± 3.26 Kcal/mol), and much lower affinities than Delta RBD (-42.76 ± 2.38 Kcal/mol). Further analysis revealed that Omicron N501Y increase ACE2 binding but Q493K and Q498R decrease ACE2 binding. In addition, Omicron RBD might escape the launched monoclonal antibodies (mAbs) Etesevimab and clinical BD-368-2 but may still sensitive to the launched mAbs Bebtelovimab.

Content

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